Tumor infiltrating lymphocytes express multiple immune checkpoints and co-stimulatory receptors. Xencor’s bispecific tumor microenvironment (TME) activators seek to more effectively reactivate these tumor-killing T cells by engaging multiple T-cell targets simultaneously. This approach eliminates the need for the multiple antibodies and allows for more selective targeting of T cells with high checkpoint expression, which may potentially improve the therapeutic index of combination immunotherapies.
XmAb104 (previously XmAb23104) is a bispecific antibody that simultaneously targets PD-1, an immune checkpoint receptor, and ICOS, an immune co-stimulatory receptor, and is designed to promote tumor-selective T-cell activation. Xencor’s XmAb® Bispecific Fc Domain serves as the scaffold for these two antigen binding domains and confers long circulating half-life, stability and ease of manufacture on XmAb104. XmAb bispecific Fc domains have been engineered to eliminate Fc gamma receptor (FcγR) binding, with the intent to prevent activation and/or depletion of T cells via engagement by FcγR-expressing cells. In preclinical studies, synergistic PD-1 blockade and ICOS co-stimulation with XmAb104 significantly enhanced T cell proliferation and activation, and anti-tumor activity in vivo.
Each of Xencor’s three bispecific TME activators tests a distinct mechanism of TME activation. XmAb717 and XmAb841 are also being evaluated in Phase 1 clinical studies.